miR-200a attenuated oxidative stress, inflammation, and apoptosis in dextran sulfate sodium-induced colitis through activation of Nrf2

IntroductionOxidative stress and inflammatory responses are critical factors in ulcerative colitis disease pathogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) modulates oxidative stress and suppresses inflammatory responses, and the protective benefits of Nrf2 activation have been associated with the therapy of ulcerative colitis. MicroRNA-200a (miR-200a) could target Kelch-like ECH-associated protein 1 (Keap1) and activate the Nrf2-regulated antioxidant pathway. Nevertheless, whether miR-200a modulates the Keap1/Nrf2 pathway in dextran sulfate sodium (DSS)-induced colonic damage is unknown. Here, our research intends to examine the impact of miR-200a in the model of DSS-induced colitis.MethodsPrior to DSS intervention, we overexpressed miR-200a in mice for four weeks using an adeno-associated viral (AAV) vector to address this problem. ELISA detected the concentration of inflammation-related cytokines. The genes involved in inflammatory reactions and oxidative stress were identified using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot, and immunofluorescence. Moreover, we applied siRNAs to weakened Nrf2 expression to confirm the hypothesis that miR-200a provided protection via Nrf2.ResultsThe present study discovered miR-200a down-regulation, excessive inflammatory activation, enterocyte apoptosis, colonic dysfunction, and Keap1/Nrf2 antioxidant pathway inactivation in mouse colitis and NCM460 cells under DSS induction. However, our data demonstrated that miR-200a overexpression represses Keap1 and activates the Nrf2 antioxidant pathway, thereby alleviating these adverse alterations in animal and cellular models. Significantly, following Nrf2 deficiency, we failed to observe the protective benefits of miR-200a against colonic damage.DiscussionTaken together, through activating the Keap1/Nrf2 signaling pathway, miR-200a protected against DSS-induced colonic damage. These studies offer an innovative therapeutic approach for ulcerative colitis

The role of Nrf2 in the pathogenesis and treatment of ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease involving mainly the colorectal mucosa and submucosa, the incidence of which has been on the rise in recent years. Nuclear factor erythroid 2-related factor 2 (Nrf2), known for its key function as a transcription factor, is pivotal in inducing antioxidant stress and regulating inflammatory responses. Numerous investigations have demonstrated the involvement of the Nrf2 pathway in maintaining the development and normal function of the intestine, the development of UC, and UC-related intestinal fibrosis and carcinogenesis; meanwhile, therapeutic agents targeting the Nrf2 pathway have been widely investigated. This paper reviews the research progress of the Nrf2 signaling pathway in UC

Role of the ISKpn element in mediating mgrB gene mutations in ST11 hypervirulent colistin-resistant Klebsiella pneumoniae

BackgroundColistin has emerged as a last-resort therapeutic against antibiotic-resistant bacterial infections, particularly those attributed to carbapenem-resistant Enterobacteriaceae (CRE) like CRKP. Yet, alarmingly, approximately 45% of multidrug-resistant Klebsiella pneumoniae strains now manifest resistance to colistin. Through our study, we discerned that the synergy between carbapenemase and IS elements amplifies resistance in Klebsiella pneumoniae, thereby narrowing the existing therapeutic avenues. This underscores the instrumental role of IS elements in enhancing colistin resistance through mgrB disruption.MethodsFrom 2021 to 2023, 127 colistin-resistant Klebsiella pneumoniae isolates underwent meticulous examination. We embarked on an exhaustive genetic probe, targeting genes associated with both plasmid-mediated mobile resistance-encompassing blaKPC, blaNDM, blaIMP, blaVIM, blaOXA-48-like, and mcr-1 to mcr-8-and chromosome-mediated resistance systems, including PhoP/Q, PmrA/B, and mgrB. PCR amplification revealed the presence of virulence-associated genes from the pLVPK plasmid, such as rmpA, rmpA2, iucA, iroB, and peg344. mgrB sequencing was delegated to Sangon Biotech, Shanghai, and the sequences procured were validated using BLAST. Our search for IS elements was navigated through the IS finder portal. Phenotypically, we harnessed broth microdilution (BMD) to ascertain the MICs of colistin. To sketch the clonal lineage of mgrB-mutated CoR-Kp isolates, sophisticated methodologies like MLST and PFGE were deployed. S1-PFGE unraveled the intrinsic plasmids in these isolates. Our battery of virulence assessment techniques ranged from the string test and capsular serotyping to the serum killing assay and the Galleria mellonella larval infection model.ResultsAmong the 127 analyzed isolates, 20 showed an enlarged mgrB PCR amplicon compared to wild-type strains. These emerged over a three-year period: three in 2021, thirteen in 2022, and four in 2023. Antimicrobial susceptibility tests revealed that these isolates consistently resisted several drugs, notably TCC, TZP, CAZ, and COL. Additionally, 85% resisted both DOX and TOB. The MICs for colistin across these strains ranged between 16 to 64 mg/L, with a median of 40 mg/L. From a genetic perspective, MLST unanimously categorized these mgrB-mutated CoR-hvKp isolates as ST11. PFGE further delineated them into six distinct clusters, with clusters A and D being predominant. This distribution suggests potential horizontal and clonal genetic transmission. Intriguingly, every mgrB-mutated CoR-hvKP isolate possessed at least two virulence genes akin to the pLVPK-like virulence plasmid, with iroB and rmpA2 standing out. Their virulence was empirically validated both in vitro and in vivo. A pivotal discovery was the identification of three distinct insertion sequence (IS) elements within or near the mgrB gene. These were:ISKpn26 in eleven isolates, mainly in cluster A, with various insertion sites including +74, +125, and an upstream −35.ISKpn14 in four isolates with insertions at +93, −35, and two upstream at −60.IS903B present in five isolates, marking positions like +74, +125, +116, and −35 in the promoter region. These diverse insertions, spanning six unique locations in or near the mgrB gene, underscore its remarkable adaptability.ConclusionOur exploration spotlights the ISKpn element’s paramount role in fostering mgrB gene mutations in ST11 hypervirulent colistin-resistant Klebsiella pneumoniae. Employing MLST and PFGE, we unearthed two primary genetic conduits: clonal and horizontal. A striking observation was the ubiquitous presence of the KPC carbapenemase gene in all the evaluated ST11 hypervirulent colistin-resistant Klebsiella pneumoniae strains, with a majority also harboring the NDM gene. The myriad mgrB gene insertion locales accentuate its flexibility and the overarching influence of IS elements, notably the pervasive IS5-like variants ISKpn26 and IS903B. Our revelations illuminate the escalating role of IS elements in antibiotic resistance within ST11 hypervirulent colistin-resistant Klebsiella pneumoniae, advocating for innovative interventions to counteract these burgeoning resistance paradigms given their profound ramifications for prevailing treatment modalities

Default risk, state ownership and the cross-section of stock returns: evidence from China

We apply a structural model to estimate firm-level default risk in China and investigate the stock return predictability of default risk and the moderating effects of state ownership for the sample period from 2003 to 2015. We show unique evidence that in China, default risk is positively associated with expected stock returns and state ownership matters considerably to the return predictability of default risk. We find investors of state-owned enterprises (SOEs) are not compensated appropriately in China despite of their higher default risk exposure. Our empirical evidence supports the conjecture on shareholder advantages and suggests that a strong bargaining power of equity holders would have a negative impact on stock returns

Short-selling activity and return predictability: evidence from the chinese stock market

We examine the informativeness of short selling in the Chinese stock market based on monthly and daily short-interest data from January 2011 to July 2018. We find that short selling negatively predicts future stock returns in China. The pattern is robust when controlling for firm size, book-to-market ratio, and liquidity. A long-short strategy using a short-interest ratio (SIR)—shares shorted to shares outstanding—generates a 0.865% monthly return. We also document that return predictability is stronger when short selling is restricted. Meanwhile, we examine the information content of short-selling activity, and we confirm that the significant negative relationship between preannouncement short activity and post-announcement period returns

Macroeconomic conditions, corporate default, and default clustering

This study investigates how, and to what extent, macroeconomic conditions interact with corporate default in the US industrial sector from 1980 to 2014. Using an extensive data set of macro-level and micro-level variables, we construct five categories of indicators and measure macroeconomic conditions by investigating the comovements within each category of indicator. We find macroeconomic conditions have bidirectional causal interaction with corporate defaults across different economic regimes, reflecting the existence of feedback causality. Moreover, we show that macroeconomic indicator constructed using the least absolute shrinkage and selection operator (LASSO) approach shows superior explanatory power as well as predictive power for default clustering, indicating that movements of these indicators cause correlated changes in firms’ default rates. Overall, our study provides support for literature on default probability estimation from a macroeconomic perspective

Microclimate Effect of Artificial Caragana microphylla Communities in Horqin Sandy Land

Caragana microphylla is one of the key species for vegetation restoration in Horqin Sandy Land. Adopting field investigation and outdoor experiments, the microclimate effect of artificial C. microphylla communities with different restoration years were studied by observing wind velocity, air temperature, relative humidity and soil temperature. The results show that: (1) Caragana microphylla community has an obvious wind-breaking effect near ground surface. Compared with shifting dunes, the wind velocity in the 6-year-old and 11-year-old C. microphylla shrubs at the height of 30 cm separately decreases by 71.9% and 76.0%. (2) Mean daily temperature in the 6-year-old and 11-year-old C. microphylla communities is 3.7 ℃ and 4.9 ℃ lower than in shifting dunes, respectively. (3) The relative humidity of air in the Caragana microphylla shrubs is higher than in shifting dunes. (4) Soil temperature in C. microphylla plantation is lower than in shifting dunes. These results are significant in further exploring material and energy exchange near surface layer of artificial vegetation in the extremely arid condition

The impact of green technology innovation on carbon dioxide emissions:The role of local environmental regulations

Environmental pollution has become a global issue attracting ever-increasing attention. Green technology innovation (GTI) is considered an effective strategy in countering this problem and helping achieve sustainability goals. However, the market failure suggests that intervention from the government is necessary to promote the effectiveness of technological innovation and hence, its positive social impacts on emissions reduction. This study investigates how the environmental regulation (ER) influences the relationship between green innovation and CO2 emissions reduction in China. Employing data from 30 provinces from the period 2003 to 2019, the Panel Fixed-effect model, the Spatial Durbin Model (SDM), the System Generalised Method of Moments (SYS-GMM) and the Difference-In-Difference (DID) models are applied to take issues relating to endogeneity and spatial impact into consideration. The results indicate that environmental regulations positively moderate the impact of green knowledge innovation (GKI) on CO2 emissions reduction but have a much weaker moderation effect when green process innovation (GPI) is considered. Among different types of regulatory instruments, investment-based regulation (IER) is the most effective in promoting the relationship between green innovation and emissions reduction, followed by command-and-control-based regulation (CER). Expenditure-based regulation (EER) is less effective and can encourage short-termism and opportunistic behaviour among firms, who can accept the paying of fines as a cheaper cost over the short-term than investment in green innovation. Moreover, the spatial spillover effect of green technological innovation on carbon emissions in neighbouring regions is confirmed, in particular when IER and CER are implemented. Lastly, the heterogeneity issue is further examined by considering differences in the economic development and the industrial structure across different regions, and the conclusions reached remain robust. This study identifies that the market-based regulatory instrument, IER, works best in promoting green innovation and emissions reduction among Chinese firms. It also encourages GKI which may assist firms in achieving long-term sustained growth. The study recommends further development of the green finance system to maximise the positive impact of this policy instrument

PowerBridge: Covert Air-Gap Exfiltration/Infiltration via Smart Plug

Power lines are commonly utilized for energy transmission, and they serve as a conduit for data exfiltration or infiltration in some specific scenarios. This paper explores the feasibility of establishing bidirectional communication between a modified plug and the equipment power line within an air-gapped network organization and with external entities. Bidirectional air-gap communication includes two scenarios, the data leak from air-gapped networks and the transmission of external data to air-gapped networks, namely, exfiltration and infiltration. In the exfiltration scenario, software in the air-gapped networks modulates and encodes data by manipulating the power consumption of the equipment during transmission, which is then sent outside through the power line. The device utilizes a smart plug power meter to record current fluctuations and subsequently decode any leaked data. In the infiltration scenario, a smart plug is used to control the power supply status of a device’s power cord, enabling data encoding and decoding by turning the power supply on and off. The software in the air-gapped equipment captures and decodes the power supply status to infiltrate. We discuss relevant literature and provide scientific background on smart plugs and power line communication. We simulate the communication scenario, propose a communication scheme, and present data modulation techniques as well as a communication transmission protocol for air-gap channels. Our evaluation of the PowerBridge air-gap channels demonstrates that data can leak from the air-gapped computer into the power line at an approximate rate of 30 bps, which can be captured by the smart plug. Additionally, it is possible for data to penetrate from the smart plug into air-gapped networks at a speed exceeding 1 bps